Activation of arachidonate release and cytosolic phospholipase A(2) via extracellular signal-regulated kinase and p38 mitogen-activated protein kinase in macrophages stimulated by bacteria or zymosan

The mitogen-activated protein kinases (MAP kinases), extracellular signal-r egulated kinase (ERK) and p38, can both contribute to the activation of cyt osolic phospholipase A(2) (cPLA(2)) We have investigated the hypothesis tha t ERK and p38 together or independent of one another play roles in the regu lation of cPLA(2) in macrophages responding to the oral bacterium Prevotell a intermedia or zymosan. Stimulation with bacteria or zymosan beads caused arachidonate release and enhanced in vitro cPLA(2) activity of cell lysate by 1.5 and 1.7-fold, respectively, as well as activation of ERK and p38. Th e specific inhibitor of MAP kinase kinase, PD 98059, and the inhibitor of p 38, SE 203580, both partially inhibited cPLA(2) activation and arachidonate release induced by bacteria and zymosan. Together, the two inhibitors had additive effects and completely blocked cPLA(2) activation and arachidonate release. The present results demonstrate that ERK and p38 both have import ant roles in the regulation of cPLA(2) and together account for its activat ion in P. intermedia and zymosan stimulated mouse macrophages.